A Phase II Trial of ZD1839 (Iressa®) in Metastatic Neuroendocrine Tumors

Inclusion Criteria:

- Histologically confirmed metastatic neuroendocrine neoplasms or histologic
confirmation of primary neuroendocrine tumor with clear clinical evidence of
metastases

- Measurable disease

- Radiographic evidence of disease progression, following any prior systemic therapy,
chemoembolization, embolization, or observation; for eligibility purposes, disease
progression will be defined as follows:

- Either of the following documented by comparison of the on-study radiographic
assessment with a prior assessment of the same type performed within the
previous 60 calendar weeks:

- Appearance of a new lesion

- At least 20% increase in the longest diameter (LD) of any previously
documented lesion or an increase in the sum of the LDs of multiple lesions
in aggregate of 20%

- ≥4 weeks from the completion of major surgery, chemotherapy or other systemic therapy
and hepatic artery embolization/chemoembolization to study registration

- ≥3 weeks from the completion of radiation therapy to study registration

- Recovered sufficiently from side effects of prior therapy

- Absolute neutrophil count (ANC) ≥ 1000/mm3

- PLT ≥ 75,000/ mm3

- Hgb ≥ 8.0 g/dL

- Total bilirubin ≤ 2 x upper normal limit (UNL)

- Alkaline phosphatase ≤ 3 x UNL (5 x UNL if liver metastases present)

- AST ≤ 3 x UNL (≤ 5 x UNL if liver metastases present)

- Creatinine ≤ 1.5 x UNL

- ECOG performance score (ps) ≤ 2

- Life expectancy ≥ 24 weeks

- Capable of understanding the investigational nature, potential risks and benefits of
the study and able to provide valid informed consent

Exclusion Criteria:

- Thyroid carcinoma of any histology or pheochromocytoma/paraganglioma

- Any of the following as this regimen may be harmful to a developing fetus or nursing
child:

- Pregnant women

- Breastfeeding women

- Men or women of childbearing potential or their sexual partners who are
unwilling to employ adequate contraception (condoms, diaphragm, birth control
pills, injections, intrauterine device [IUD], surgical sterilization,
subcutaneous implants, or abstinence, etc.)

- NOTE: The effects of the agent(s) on the developing human fetus at the
recommended therapeutic dose are unknown

- Anaplastic or high-grade histology

- Any of the following prior therapies:

- > 1 prior systemic chemotherapy regimen (chemoembolization not counted as
systemic chemotherapy)

- Prior EGFR targeted regimen (e.g. OSI-774, EKB-569, ZD1839)

- < 4 weeks from last Interferon injection

- < 2 weeks from last octreatide short acting injection or < 6 weeks long acting
injection; Note: concurrent octreatide allowed if stable dose has been
administered for ≥1 month, there is documented tumor progression on the current
dose, and there is no current plan for increasing dose • Other concurrent
treatment considered investigational

- Concurrent chemotherapy or radiation therapy

- Any of the following:

- Gastrointestinal tract disease resulting in an inability to take oral medication
(e.g. dysphagia or inability to swallow capsules intact).

- Requirement for IV alimentation

- Prior procedures clearly adversely affecting intestinal absorption

- Active peptic ulcer disease

- Failure to fully recover from adverse effects of prior therapies regardless of
interval since last treatment

- Known abnormality of cornea, such as:

- History of dry eye syndrome or Sjogren syndrome

- Congenital abnormality

- Abnormal slit-lamp examination using a vital dye (e.g.: fluorescein or
Bengal-rose)

- Abnormal corneal sensitivity test (Schirmer test)

- Uncontrolled intercurrent illness including, but not limited to:

- Ongoing or active infection

- Symptoms of congestive heart failure

- Unstable angina pectoris, cardiac arrhythmia

- Psychiatric illness/social situation that would limit compliance with study
requirement

- Known brain metastases; Note: These patients are excluded from this clinical trial
because of their poor prognosis and because they often develop progressive neurologic
dysfunction that would confound the evaluation of neurologic and other adverse events

- Known HIV-positive patients receiving combination anti-retroviral therapy; Note:
These patients are excluded from the study because of possible pharmacokinetic
interactions with ZD1839 and because patients with immune deficiency are at increased
risk of lethal infections when treated with marrow-suppressive therapy; appropriate
studies will be undertaken in patients receiving combination and anti-retroviral
therapy when indicated

- Concurrent or recent use (≤ 7 days prior to ZD1839 administration) of phenytoin,
carbamazepine, barbiturates, rifampicin, oxcarbazepine, rifapentine, modafinil, or
St. John's Wort; Note: Because these drugs induce CYP3A4 enzymes and can cause
reductions in ZD1839 plasma concentrations below levels thought to be biologically
active, patients with concurrent or recent use of these drugs are excluded from the
study

- History of other invasive malignancy ≤ the previous 3 years, except for adequately
treated basal cell or squamous cell skin cancer, or carcinoma in situ of the cervix